The invention relates to the filtration of a blood products and more specifically, to a filtration media for the removal of leukocytes from blood products.
The technology of human blood transfusion has improved significantly in recent years. Unlike early transfusion practices that involved the transfusion of units of whole blood, a recipient will now typically only receive that fraction of whole blood that is needed under the particular circumstances. For example, a patient in need of red blood cells can receive a transfusion of packed red cells (pRBC) or concentrated red cells (cRBC) and a patient in need of platelets can receive a transfusion of platelet concentrate, while a patient in need of increased blood volume can receive a transfusion of plasma or a plasma product. For transfusion purposes, a donated whole blood supply is typically separated into the aforementioned three components by centrifugation. In addition to these basic components, whole blood also contains various types of white blood cells, collectively known as leukocytes, which are present in substantial levels in both RBC and platelet suspensions.
Leukocytes, which include for example, granulocytes, macrocytes and lymphocytes, function to provide protection against a wide range of bacterial and viral infections. As such, the transfusion of a leukocyte-containing product might be expected to be beneficial in the therapy of immunosuppressive diseases. To the contrary however, research has shown that patients who received granulocyte transfusions will quickly develop such adverse effects as rigor, nausea, headache, and high fever, and shortly thereafter, will reject the transfused cells. In addition, it is known that certain viruses are resident in leukocytes and as a result, transfusion of infected cells to an immunosuppressed patient has the potential of inducing a life-threatening viral disease. Graft versus Host disease, as well as certain viruses, such as HIV, HTLV1 and CMV, among others, are now believed to be transmitted by the transfusion of infected leukocytes. Although a unified world-wide standard for acceptable leukocyte levels in donated blood products has yet to emerge, it is generally accepted that a majority of severe adverse effects may be reduced or prevented if the leukocyte content is reduced to, for example, less than one to five million leukocytes per unit of red cells transferred. Accordingly, it is therefore quite desirable to provide a clinically effective means for significantly and efficiently reducing the leukocyte content of donated biological fluids, namely, whole blood and blood component products.
A typical unit of pRBC averaging about 350 mL in volume contains between about 1xc3x97109 and 5xc3x97109 leukocytes. Differences in the leukocyte content are largely attributable to differences in the donor. According to internationally accepted standards, a unit of RBC must contain no more than 106 leukocytes for it to qualify as being leukocyte depleted. The corresponding leukocyte depletion rate required is thus on the order of 99.9% and 99.99%. Commercially viable filters should routinely deliver the higher level of leukocyte depletion to accommodate for normal variations in the source, filtration conditions, and age of the blood being filtered.
Various methods for removing leukocytes from biological fluids are known in the art and include for example, repeated centrifugation, saline washing, filtration and agglutinant incorporation/sedimentation. Of these methods, filtration has been accepted as the removal technique of choice. A typical leukocyte filtration process involves passing a leukocyte-rich blood product through a filter comprised of a material that adsorbs leukocytes and/or entraps them within the filter and obtaining a leukocyte-depleted filtered product without altering the physical and therapeutic characteristics of other blood components present in the product.
Leukocyte filtration of blood products may rely primarily on two mechanisms: sieving and adhesion. Sieving is typically caused by the mechanical entrapment of leukocytes within a filter material, while adhesion typically results from interactions between the leukocyte cell surface and the filter material itself. Conventional leukocyte reduction devices may involve a depth filtration medium that is comprised of various diameter fibers entwined into a web-like matrix, which provides for tortuous flow paths that offer different resistance to cells of different sizes and shapes, as well as substantial internal surface areas for preferential leukocyte adhesion. To accomplish acceptable selectivity between leukocytes and red blood cells, media of this type typically exhibit relatively small average pore sizes; thus resulting in modest flow rates through the filtration device.
U.S. Pat. No. 5,454,946 (the xe2x80x9c""946 patentxe2x80x9d) describes a leukocyte filter material that is comprised of a matrix of interlocked fibers having spaces between adjacent interstices wherein fibrillated particles of polymeric material are disposed within the spaces and a thermoplastic binder is disposed at least at cross-over sections of the matrix fibers. This patent states that the weight ratio of the fibrillated particles to the matrix fibers must be between about 1:99 and 40:60, and especially between about 5:95 and 40:60, and preferably less than about 20:80. If that ratio is less than about 3:97, the additional surface area supplied by the fibrillated particles is marginal for desired leukocyte filtration, and at below about 1:99, the surface area is simply not sufficient to achieve a minimum desired depletion of leukocytes, i.e., at least a 70% depletion. This patent further teaches that with increasing ratios of fibrillated particles to matrix fibers, the depletion of leukocytes from blood will be correspondingly increased, such that at a ratio of about 5:95, the depletion percentage will be close to about 90%, and at about 10:90, the depletion may be as high as about 99%, for some modes of blood filtration.
Thus, the ""946 patent teaches that the filter media described therein achieves minimum desired leukocyte depletion if the weight ratio of fibrillated fibers to matrix fibers is within a specifically defined range, about 1:99 to 40:60. Moreover, leukocyte depletion rates increase with increasing weight ratios with optimal performance occurring at a weight ratio of 10:90. Conversely, leukocyte depletion rates decrease with decreasing weight ratio and that insufficient leukocyte reduction occurs at a weight ratio of fibrillated fibers to matrix fibers of less than about 1:99. According to the ""946 patent, the desired minimum leukocyte reduction rate is 70%. In reality, however, leukocyte depletion devices, in order to meet commercial and medical requirements, typically should achieve leukocyte reduction rates of 99.9% or higher. Therefore, the ""946 patent does not describe a leukocyte depletion device which achieves commercially and medically acceptable leukocyte filtration rates with a weight ratio of fibrillated fibers to matrix fibers of less than about 1:99.
The ""946 patent also describes the use of fibrillated particles having a surface area of 30 or 50 or 70 square meters per gram in a filtration media and suggests that the use of surface area particles up to 100 square meters per gram may be used in a way where the particles are still retained in the matrix. However, the ""946 patent does not teach or contemplate how one may achieve acceptable and/or superior leukocyte reduction using fibrillated particles of a higher surface area such as 100 m2/g, or even how to obtain fibrillated particles of such a high surface area.
We have discovered a way to achieve leukocyte reduction rates of substantially greater than 70% even when using a weight ratio of fibrillated fibers or particles to matrix fibers of less than or equal to about 1:100. We have also discovered that leukocyte reduction rates of 99.99% and higher may be achieved at a weight ratio of less than or equal to about 1:100 including, but not limited to, weight ratios below 1:200. We have also found a way to incorporate a high-specific surface area component beyond those previously used, to achieve an unexpected and advantageous increase in leukocyte removal, contrary to the teachings of the ""946 patent. We have found a way to increase the surface area of fibrillated particles to an ultra-high level and to incorporate those fibers into fiber matrix to achieve commercially and medically acceptable leukocyte reduction rates. While the art teaches a number of different approaches to leukocyte reduction filter materials, and attempts to identify key parameters governing performance of those materials, it has not hitherto been recognized that incorporating a very high specific internal surface area component into a medium at extremely low weight ratios can lead to significantly improve leukocyte depletion performance.
The present invention provides a high capacity leukocyte reduction filtration medium for the effective and efficient reduction of the leukocyte content of donated blood products, prior to transfusion. As used herein, the term xe2x80x9cblood productsxe2x80x9d is intended to include whole blood and components thereof, such as, for example, plasma, red blood cells and platelets.
The construction of the filtration medium of the present invention incorporates a high specific surface area component into a relatively open porous fibrous matrix, thereby creating a multitude of leukocyte adhesion sites, while at the same time providing a fast filtration flow rate. This construction promotes the adsorption of leukocytes onto the filtration medium, and compliments sieving as a means of leukocyte removal, while allowing red blood cells to flow through the filtration medium with minimal interference.
In one embodiment, the principles of the present invention provide a high capacity leukocyte reduction filtration medium comprising a matrix of fibers and a plurality of components distributed amongst the matrix fibers, wherein the weight ratio of the components to the matrix fibers to is less than or equal to about 1:100, preferably less than about 1:150, and more preferably, less than about 1:200.
The components distributed amongst the matrix fibers have a high specific surface area, much greater than that of the matrix fibers. The high specific surface area components provide the medium with the capability of removing 99.99% or more of leukocytes present in a blood product. The high surface area components may be in the form of highly fibrillated fibers, fibrils, or highly fibrillated particles preferably having spherical or rounded shapes. Preferably, the components such as the highly fibrillated fibers or fibrils have a high specific surface area, e.g., at least about 100 m2/g, and more preferably, at least about 120 m2/g. The average diameter of the fibrils is preferably less than about 0.05 xcexcm, and more preferably, less than about 0.035 xcexcm. The components function to increase the surface area of the filtration media and increase the effective surface area for leukocyte adhesion. Thus, the components may comprise any configuration and/or materials that will result in increased surface area and leukocyte adhesion sites. Any such components are intended to be within the scope of this invention.
High performance filtration systems are designed with three key objectives: (1) consistently meeting accepted standards for the leukocyte depleted blood product; (2) minimizing the amount of loss of the blood product due, for example, to capillary hold up in the filter medium; and (3) completing the filtration within a short period of time relative to standard operating procedures. A filter medium with high intrinsic leukocyte removal capacity while offering low resistance to passage of the blood product helps accomplish these objectives in a relatively small filter device.
With this combination of increased specific surface area of the components on the leukocyte reduction filtration medium of the present invention may provide at least a ten thousand fold reduction of leukocytes, i.e., a 99.99% efficiency in a filtered blood product and a high flow rate of blood product whereby a 350 mL unit of red blood cells, for example, may be processed in less than about 20 minutes.
The principles of the present invention also provide a method for removing leukocytes from blood products. In one embodiment, the method comprises passing a leukocyte-containing blood product through a leukocyte reduction filtration medium comprising a matrix of fibers and a plurality of components distributed amongst the fibers as described herein and recovering a leukocyte-depleted blood product.